Compression Connection

ABSTRACT

A chromatography and fluidic device with connections capable of automated component changing, diagnostic leak and current sensing. The chromatography-electrospray device contains a chromatography column, a pre-column, a spray emitter, or other fluidic component imbedded within one or more inserts. The inserts are robotically placed in receiving hardware, and a “plug and play” compression fitting connection mechanism makes the fluidic seals in an automated fashion. A plurality of sensors capable of detecting leaks is situated in the device near leak-prone regions. The electrospray emitter has a current sensing electrode in proximity of the electrospray region, capable of detecting the electrospray current. In conjunction with an electronics system, these sensors allow for system and component diagnostics. The diagnostic information may then be used for manual or automated system repair.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of application Ser. No. 11/837,989,filed Aug. 13, 2007, which claims the benefit of U.S. ProvisionalApplication Ser. No. 60/822,231, filed Aug. 12, 2006, and their entirecontents are hereby incorporated by reference.

FIELD OF THE INVENTION

The present invention relates generally to a chromatography and fluidicssystem, and more specifically to a chromatography electrospray systemwith “plug and play” connections along with integrated leak and currentsensors for monitoring and diagnosing the status of ultra-low levelfluidic manipulation. In particular, the present invention relates to anintegrated nanofluidic separation system and electrospray device. Thisachieves a significant advantage over other conventional low-flowchromatography electrospray systems that lack the means and technologyto diagnose individual component performance and operation. This presentinvention allows for component diagnostics in chromatography and fluidicsystems. The present invention further provides the ability to implementan automated replacement system capable of making fluidic connections.Furthermore, the connections of the invention are automatically sealedwith the proper force, eliminating the need for the user to guess thecorrect amount of compression force to apply when tightening fittings.

BACKGROUND OF THE INVENTION

Nanoflow liquid chromatography (“nanoLC”) is a technique for resolvingvery complex samples that are limited in concentration or volume.Predominantly the technique is used for proteomic studies where it isoften used in combination with mass spectrometry. NanoLC of either wholeproteins or a proteolytic digest is performed to separate very complexsamples, and then the flow from the nanoLC is directed into a massspectrometer. The advantages of nanoLC mass spectrometry as compared toconventional higher flow rate chromatography include lower sample volumerequirements and higher sensitivity. NanoLC separation reduces thecomplexity of the sample by resolving the different components of asample, allowing the mass spectrometer to obtain mass spectra for manycomponents contained in the sample.

A liquid chromatography/mass spectrometry (LC/MS) system is composed ofa pumping system, an autosampler injection system, a chromatographycolumn(s), a means of ionization, and a mass spectrometer detector. Thepumping system delivers mobile phase (solvents) at a user defined flowrate, typically ranging from 20 nL/min to 6 mL/min. Mobile phasesgenerally consist of two solvents where one is predominantly aqueous(water) in nature and the other is predominantly organic in nature(methanol, acetonitrile, isopropanol, etc). Additives such as formicacid, acetic acid, ammonium acetate, ammonium hydroxide, etc, can alsobe present in the mobile phase. The pumping system delivers thedifferent solvents of the mobile phase in a precise way that is referredto as the gradient. For an analysis using a reversed-phase column, thegradient typically begins with high aqueous solvent and graduallyorganic solvent is introduced, while the overall flow rate remainsconstant. By the end of the analysis, the mobile phase content ispredominantly organic solvent.

The target sample of interest is introduced to the flow stream by theautosampler injection system. This system typically consists of anaspiration needle and a valve. The system aspirates the sample ofinterest using the needle and subsequently injects the sample into theinjection valve. This valve has a sample loop that can be 1 microliterto 10 milliliters in volume, and is filled with the sample of interest.Then the valve is switched from the “load” position to the “inject”position, and the plug of sample from the loop becomes in-line with theflowing mobile phase from the pumping system. The mobile phase displacesthe sample plug from the loop and pushes it into the analysis path. Atthis point the pumps would be early in the gradient program, so that thesample plug is in predominantly aqueous solvent.

The sample continues flowing downstream and reaches the column. As themobile phase is predominantly aqueous in nature, the sample adsorbs tothe stationary phase at the top of the reversed-phase column. As theanalysis is performed the solvent composition of the mobile phasebecomes increasingly organic in content. As this occurs, mass transferof the retained molecules occurs between the stationary and mobilephases. The components of the sample make their way through the columnat different rates, and thus the sample is chromatographically resolved.

The various components of the sample exit the column at different timepoints in the flowing mobile phase. As the mass spectrometer is onlyable to detect ions, not neutral molecules, the sample components mustbe converted to ions prior to entering the mass spectrometer. One meansof generating ions is electrospray ionization, which at lower flow ratesis referred to as nanoelectrospray ionization. In brief, a high voltageis applied to the column effluent containing the sample components ofinterest. The high voltage generates highly charged droplets and throughsubsequent droplet evaporation and droplet fission, desolvated ions areformed.

The ions then enter the mass spectrometer detector. The massspectrometer determines the mass-to-charge ratio of the ions. Many ofthese instruments perform tandem mass spectrometric measurements,allowing structural information of the ion to be determined.

At the end of the analysis, the column is washed with high organicsolvent and is then re-equilibrated in the aqueous mobile phase. Anautosampler routine is used to wash the injection needle and sample loopseveral times to help minimize sample-to-sample cross-contamination andcarryover. At this point a second analysis can be performed.

NanoLC is typically performed at flow rates between 5-500 nL/min. Theselow flow rates necessitate the use of special pumping systems,chromatography columns, and spray emitters used for the electrosprayionization (“ESI”) interface to the mass spectrometer. Even with thespecialty equipment currently available nanoLC is very difficult toperform. Making connections with micron size tubing requires userintervention to tighten fittings. As there is no feedback in the system,the user must guess the correct amount of tightening to make the fittingleak-free. Generally, this leads to over tightening of the fittingswhich may prevent leaking, however, simultaneously creates a secondaryproblem. The over tightening can either damage the tube, the fitting, orthe fragile capillaries. Connecting nanoLC columns is especiallydifficult as the fragile columns are prone to damage due to frits,stationary phase within the column, or other material in the tube beingcrushed, cracked, or over compressed. Additionally, the rotation of theconventional fitting can cause the tube or capillary to be twisted,resulting in grinding or damage from the twisting itself.

Connections between the pumping system and column, and between thecolumn and spray emitter are especially prone to leaks. Often the leaksare very difficult to detect as evaporation renders the leakunperceivable at the low flow rate or the liquid build up is so small itis difficult to observe. This holds true for both chip-basedmicrofluidics and conventionally assembled components. Leaks at theseconnections can be due to user error in making connections, or due to achange in the system backpressure which can result from a clogged columnor spray emitter. Further challenges of nanoLC include columnirreproducibility, spray irreproducibility, poorly optimized solventgradient separation, insufficient column regeneration period, and poorlyoptimized emitter position. Conventional fittings are thread-basedrequiring rotation of the ferrule, and subsequently the tubing, togenerate a seal. The applied twisting motion causes tubing ends to grindagainst surfaces creating jagged ends and producing particulates thatsubsequently clog and contaminate fragile components downstream. Thechallenges associated with nanoLC results in the technique only beingsuccessfully used by very few expert users.

Although various research and apparatuses have attempted to reduce thedifficulty of conducting nanoLC there is still a need for a simple,robust system with easy to change components and integrated diagnosticsensors for identifying malfunctions in the dynamic fluidic system. Thisincludes conventional, microfluidic, and nanofluidic-based fluidicsystems.

Additionally, current technologies provide limited measurements at thepumping level, which is not indicative of component status at thechromatography and electrospray level. Therefore, the current technologylacks the ability to indicate the malfunction location. In addition tonot being able to diagnose the problem, these current technologies lackthe ability to automatically change-out the appropriate components dueto both lack of information and due to instrument design involvingconnecting fittings that require human intervention.

Therefore there exists a need for an automatic sealing device for makingconnections in fluidic systems to reduce potential user over tighteningand to self-align the components within the fluidic system.

There also exists a need for a prefabricated insert containing multiplefluidic components to reduce the number of connects that a user isrequired to make.

There exists a need for detecting leaks in microfluidic and nanofluidicapplications where sample size and flow rates are too small to bedetected by conventional means.

There further exists a need for fluidic system components that are easyto replace and can be interchanged by an automated process.

SUMMARY OF THE INVENTION

The present invention reduces the complexity of fluidic systems.Specifically, of nanoLC by allowing a large number of users tosuccessfully perform the technique. The invention encompasses a simple,“pop-into-place” device which has the nanoLC column and spray emitterincorporated within a single structure. Furthermore, all connections areeither pre-made or made when the user inserts the device into its holderin front of the mass spectrometer. The connections are automaticallysealed with the proper compression force, eliminating the possibilityfor the user to over or under tighten the connections. Built-in sensorsdetect any leaks in the nanoLC system, and a spray sensor monitors theelectrospray process. The present invention allows for nanoLCapplications beyond proteomics to other areas such as pharmaceuticalanalyses, forensic analyses, biomarker analyses, environmental analyses,clinical diagnostics, flow-through reactors and other areas requiringmore sensitivity and efficiency with a robust and easy-to-usetechnology.

The present invention contains receiving hardware that can accept one ormore “plug and play” components. A positioning sensor assures properinsertion and alignment of the “plug and play” components. In oneembodiment the receiving hardware has auto-insertion hardware for properplacement of the packages in the system. The receiving hardware alignsthe consumable in front of the detector for optimal detectorperformance. The hardware and consumable insert can be keyed foraccurate alignment and precise placement. This can be accomplishedthrough use of alignment features and mechanical positioning features.

A simple consumable insert or “plug and play” component is inserted intothe receiving hardware. The insert contains a nanoLC column andelectrospray emitter with integrated sensors for diagnosing system andcomponent failure for fluidic technologies where visual assessment isnot possible. The system allows for manual or automated microfluidicconnections without the need for user expertise in making difficult andcritical fluidic connections. In addition to a column and spray emitter,the insert could also contain a pre-column, a transfer line, a trap, afilter, a frit, a reactor, a union, a tee, a manifold, a mixer, avessel, a injector, an adapter, a sensor, a backpressure regulator, acoupler, a plug, a loop, a needle, a injector valve, a check valve, ametering valve, a splitting valve, a purge valve, a switching valve, anda Y-connecter.

The present invention contains sensors that operate independent of eachother, and a software program logs critical information and monitorscomponent and system operation. The information may then be used tocontinue system operation, necessitate component or system shutdown,adjust system parameters, or initiate the replacement of necessarycomponents.

The present invention is further capable of diagnosing very smallfluidic leaks and nanoflow electrospray failures at the component andsystem level for conventional, microfluidic, and nanofluidic devices.According to one aspect of the present invention, the leak sensors areintegrated into the insert and the corresponding interconnects are madeautomatically upon placement of the consumable in the acceptinghardware.

Integrating all the above features allows for a more robust and “smart”system not available with current chromatography technology.Additionally because the device integrates diagnostic features, notavailable with current technologies, the system can automaticallyidentify problematic components within a system. This contrasts today'ssystems that require high user skill to trouble shoot and whererepairing the system often involves blind substitution of parts todiagnose the problematic components. The insert can include one or moreof the chromatography devices within each insert. Thus one insert foracceptance into the receiving hardware may include one or more liquidchromatography or liquid chromatography electrospray devices. Theautomated sealing allows for component changing for fluidic applicationsin general.

The plug-and-play compression connections of the present invention canfurther be utilized to interface a vessel pre-filled with a targetsample of interest to an analysis system. Delivery of the fluid sampleto the analysis system may be via displacement using positive ornegative pressure.

BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS

The above and other objects, features, and advantages of the presentinvention will become more apparent when taken in conjunction with thefollowing description and drawings wherein identical reference numeralshave been used, where possible, to designate identical features that arecommon to the figures, and wherein:

FIG. 1 is a schematic view of a liquid chromatography/mass spectroscopysystem according to the prior art.

FIG. 2A is a representation of a compression fitting according to theprior art.

FIG. 2B is a representation of a compression fitting according to theprior art.

FIG. 3 is a representation of a compression fitting and sleeve accordingto the prior art.

FIG. 4 is a block diagram of the “plug-and-play” insert devices, thereceiving compression hardware, a fluid delivery system and fluidprocessing hardware.

FIG. 5 is a block diagram of an insert containing a target sample ofinterest, the receiving compression hardware and the fluid processinghardware.

FIG. 6 is a cross-sectional view of a tube being sealed with a ferruleand receiving port via axial force generated by the controlled forcecompression system.

FIG. 7A is a cross-sectional view of a dual-sided receiving port wheretwo separate tubes are sealed via axial force generated by thecontrolled force compression system. Both tubes are sealed with equalforce as there is only a single compression system.

FIG. 7B is a cross-sectional view of a dual-sided receiving port wheretwo separate tubes are sealed via axial force generated by thecontrolled force compression system. The tubes have independent sealingforces as there are two independent compression mechanisms and thereceiving port is braced.

FIG. 8A is a cross-sectional view of an assembly of ferrules andreceiving ports where two separate tubes are connected to a column atits inlet and outlet, the controlled force compression system compressesall of the ferrules and receiving ports providing sealed connections.

FIG. 8B is a cross-sectional view of an assembly of ferrules andreceiving ports where two separate tubes are connected to a column atits inlet and outlet, separate controlled force compression systemsindependently compress all of the ferrules and receiving ports on theinlet and outlet sides allowing for independent sealing control andcompression strength on both the inlet and outlet sides.

FIG. 9A is a cross-sectional view of an assembly of ferrules andreceiving ports where part of the assembly is contained within theinsert, the column is sealed to two separate tubes which are external tothe insert.

FIG. 9B is a cross-sectional view of an assembly of ferrules andreceiving ports where part of the assembly is contained within theinsert, the column is sealed to two separate tubes which are external tothe insert, separate controlled force compression systems, independentlycompress all of the ferrules and receiving ports on the inlet and outletsides, allowing for independent sealing control and compressionstrength.

FIG. 10A is a cross-sectional view of an assembly of ferrules andreceiving ports where part of the assembly is contained within theinsert, the controlled force compression system compresses all of theferrules and receiving ports thus providing sealed connections.

FIG. 10B is a cross-sectional view of an assembly of ferrules andreceiving ports where part of the assembly is contained within theinsert, separate controlled force compression systems independentlycompress the ferrules and receiving ports on the inlet and outlet sidesof the column, allowing for independent sealing control and compressionstrength.

FIG. 10C is a cross-sectional view of an assembly of fittings where partof the assembly is contained in a first insert and part of the assemblyis contained in a second insert.

FIG. 11 is a cross-sectional view of a tube being sealed with a ferruleand receiving port via radial movement of the controlled forcecompression system, and this movement subsequently generates axialsealing force.

FIG. 12 is across-sectional view of a dual-sided receiving port wheretwo separate tubes are sealed together with ferrules and receiving portvia radial movement of the controlled force compression system, and thismovement subsequently generates axial sealing force, the tubes aresealed with equal force as there is only a single compression system.

FIG. 13 is a cross-sectional view of a dual-sided receiving port wheretwo separate tubes are sealed together with ferrules and a receivingport via radial movement of the controlled force compression system, andthis movement subsequently generates axial sealing force, the tubes haveindependent sealing forces as there are two independent compressionmechanisms and the receiving port is braced.

FIG. 14 is a cross-sectional view of an assembly of ferrules andreceiving ports in an insert where a column is connected to two separatetubes at its inlet and outlet locations, radial movement of thecontrolled force compression system subsequently generates axial forcewhich seals all the components.

FIG. 15 is a cross-sectional view of an assembly of ferrules andreceiving ports in an insert where a column is connected by two separatetubes at the inlet and outlet locations, independent radial movement oftwo controlled force compression systems produce subsequent axial force,sealing both the inlet and outlet ends independently.

FIG. 16 is a cross-sectional view of an assembly of ferrules andreceiving ports where part of the assembly is contained within theinsert, the column is sealed to two separate tubes, both of which areexternal to the insert, and independent radial movement of threecontrolled force compression systems produce subsequent axial force,compressing and sealing the components.

FIG. 17A is a cross-sectional view showing a Tee structure with femaleends where three ferrules are engaged with a three-way receiver portusing three independently controlled force compression systems.

FIG. 17B is a cross-sectional view showing a Tee structure withferrule-like outlets where the three outlets of the Tee are engaged withthree corresponding receiver ports using three independently controlledforce compression systems.

FIG. 18 is a cross-sectional view showing a manifold with fourferrule-like outlets where the four outlets of the manifold are engagedwith four corresponding receiver ports using four independentlycontrolled force compression systems.

FIG. 19A is a cross-sectional view of a single orifice vessel having aferrule-like opening which can seal against a receiver port system whenaxial force is generated by a controlled force compression system.

FIG. 19B is a cross-sectional view of a multi-orifice vessel havingferrule-like openings which can seal against receiver ports when axialforce is generated by a controlled force compression system.

FIG. 20 is a cross-sectional view of the device containing an opticalport, light source, and light-based detector.

FIG. 21 is a cross-sectional view of the device containing ports forelectrode structures.

FIG. 22 is a cross-sectional view showing contact leak sensors withtheir distal ends located in close proximity to the seal and compressioninterface.

FIG. 23 is a cross-sectional view showing contact leak sensors locatedfurther in proximity from the seal and compression interface.

FIG. 24 is a cross-sectional view showing a non-contact, optical leaksensor using transmitted light through the leak prone regions internalto the fitting.

FIG. 25 is a cross-sectional view showing a non-contact, optical leaksensor using transmitted light, through the leak prone regions externalto the fitting.

FIG. 26 is across-sectional view showing non-contact, reflected light,optical leak sensors where the light paths operate in close proximity tothe fitting.

FIG. 27 is a cross-sectional view showing non-contact, reflected light,optical leak sensors where the light paths are further in proximity fromthe fitting.

FIG. 28 is a drawing illustrating the docking hardware and the insertwith a retractable sheath that protects exposed components.

FIG. 29A shows the insert being placed into the docking hardware and thecompression connection between these two components is about to be made.

FIG. 29B shows the compression connection between the insert and thedocking hardware.

FIG. 29C is an x-ray view of the compression connection between theinsert and the docking hardware.

FIG. 30A is a cross-sectional view with the insert placed in the dockinghardware and the sheath retracted exposing the spray emitter.

FIG. 30B shows the insert placed in the docking hardware, thecompression connection made, and the sheath retracted exposing the sprayemitter.

FIG. 31 illustrates system integration. The data system would collectfeedback from the sensors, perform robotic manipulation, and managecommunication input and output.

FIG. 32A illustrates a radial array for a plurality of inserts.

FIG. 32B illustrates a linear array for a plurality of inserts.

DETAILED DESCRIPTION OF THE INVENTION

An aspect of the present invention provides a “pop-in”, “plug-and-play”,“snap-in”, “click-in” or “quick connect” liquid chromatographyelectrospray device that requires little user expertise. In oneembodiment the “plug-and-play” device has integrated performance sensorsand detectors. The sensors allow for monitoring of performance at thecomponent and system levels, and provide the option of automated repairor consumable replacement. The “plug-and-play” connections allow forcomponents to be changed in an automated fashion or with limited userskill or know-how. The compression mechanism has a force measuringmechanism that controls the precise amount of force generated.Additionally, the system can monitor the sealing force and makeadjustments if necessary due to leaks, change in pressure requirementsor for material fatigue. It is understood that the terms“Plug-and-Play”, “Quick Connect”, “Snap-in”, “Click-in”, “Pop-in”,reference the ability to place the part or component into thecorresponding receiving hardware where the part is then integrated intothe system in an automated fashion or with limited user intervention andmay be used interchangeably. The present invention does not requirespecial tools or user know-how to make high pressure connections such ashand manipulation of fittings, ferrules, or thumb screw nuts. Thepresent invention eliminates the need for a user to determine thecorrect sealing force needed to make fragile micro and nanofluidicconnections leak tight. In one embodiment the compression system ormechanism has a controlling force system capable of applying apre-determined amount of force. Alternatively, the compression system iscapable of maintaining a given amount of force. The system may alsoinclude a force limiting system to avoid over compression.

The “plug and play” insert may be a molded or machined package or may becasted in place. The insert may contain one or more separation device,one or more electrospray device, leak sensors, or any combinationthereof. The insert may contain a retractable feature for protectingexposed components including a column end or spray emitter.

The “plug and play” connection allows for the connections of one or moreliquid or gas streams in tubing or capillaries. The connections may haveintegrated functionality within the fitting such as particle filters,frits, guard columns, trap columns, reactors, injectors, or particle,monolithic, or affinity stationary phases, or those alike. Alternativelythe inserts may have integrated functionality such as particle filters,frits, guard columns, trap columns, reactors, injectors, or particle,monolithic, or affinity stationary phases, or those alike. They may alsoinclude or interface with components such as a transfer line, aelectrospray emitter, a union, a tee, a manifold, a mixer, a vessel, anadapter, a backpressure regulator, a coupler, a plug, a loop, a needle,a sensor, a injector valve, a check valve, a metering valve, a splittingvalve, a purge valve, a switching valve, and a Y-connecter. Theconnection can connect glass, metal, polymer or polymer-based,composites, or ceramic tubing. Alternatively, structures other thantubes and capillaries could be molded and used with the connections. Inone embodiment, a fitting is attached to a column inlet to join thecolumn and a supply stream tube or capillary. The fittings can be partof a system or they may be independent of hardware if used to connectunrestricted tubing, capillaries or substrates. If the connection isintegrated into a hardware platform, the component with the connectioncan be replaced via robotics or other hardware manipulators and thecompression device can automatically compress the fittings. The fittingsmay be casted, molded, machined, monolithic in nature, or compiled frommultiple components. The fitting may hold up to 100,000 PSI, howeverthis force can increase as technology advances. The fitting receives aconstant pressure in the axial direction. The constant compressionconnection of the instant invention is less prone to leaks as comparedto the conventional thread-type chromatography connections asconventional fittings often fatigue, slip, or loosen over time andrequire additional force to be reapplied by further tightening of thefittings. The fittings may be used to connect preparative, analytical,micro, nano, and pico chromatography columns, as well as CE, CEC,capillary tubes, flow-through reactors, sample injectors, and chip-basedseparation structures and features, such as channels that are packed orunpacked.

In one embodiment the liquid chromatography electrospray system hasdisposable components that are affixed to the main instrument housing orreceiving hardware that is interfaced to an electrospray device.Independent sensors monitor and control the various components in theliquid chromatography electrospray device. The sensors allow for thedetection of various diagnostic and performance measurements such asleaks, spray current, system pressure, reaction kinetics, and flow ratein given regions of the device. The invention contains sensors thatallow for diagnostic measurements and automated repair of malfunctioningcomponents. This automation also allows for columns of variousstationary phase chemistries to be implemented without userintervention. Additionally, the electronic data system can indicate thestatus of the system by recording the sensor information or systemparameters to a remote site or user via wired or wireless communicationtechnologies. The electronic data system may also receive informationand conduct future actions based on the received information orcommands. In addition to allowing automatic change-out of inserts andcomponents, the present invention's fitting connection design allows forlow skilled users to make leak-tight connections.

Shown in FIG. 1 is a schematic view of a liquid chromatography/mossspectroscopy system according to the prior art. The liquid delivery pumpdelivers solvent A and solvent B to the column. In the sample injectionpart the sample is injected into the flow of the solvents at apredetermined time by an injector valve. The sample is then delivered toand through the column to the spray nozzle. The spray nozzle deliversthe sample to the mass spectrometer where the sample is the analyzed.The data is then sent to the data processing part and information isgenerated at the display part. The control part allows for the system tobe automated and can adjust the timing of particular operations asneeded. Additionally, an autosampler may be used to inject the sample inthe sample injection part.

FIGS. 2A and 2B are representation of a compression fitting according tothe prior art. Traditional fittings utilize frusto-conical compressionto hold tubing lengths together. Typically a singular plane of contactis made around the circumference of the tube when the 30 degree taperedferrule tip is compressed against the 45 degree interior taper of thereceiver port body. As the nut is tightened into the receiver port body,the compression is intensified. Though effective, attention to techniqueis required to make a clean, secure connection without inadvertentlycreating deformations or fractures in the tubing. These fractures wouldsubsequently generate shards of fused silica that could find their waydownstream, creating clogs and other system issues. In addition toconical force, twisting motion pushes the tubing ends toward each other.Because no radial slippage occurs, tubing ends are ground together; upongrinding, imperfections or jagged ends in cleaved tubing can producethousands of fused-silica particulates. The end result is tip cloggingand failure.

FIG. 3 is a representation of a compression fitting and sleeve accordingto the prior art. A connection is made similar to the compressionfitting in FIG. 2 with the addition of a sleeve. The sleeve surroundsthe circumference of the tube allowing for the use of a ferrule with alarger bore throughout its axial length.

Various modifications to the preferred embodiment will be readilyapparent to those skilled in the art, and the general principles definedherein may be applied to other embodiments and applications withoutdeparting from the spirit and scope of the invention. Thus, the presentinvention is not intended to be limited to the embodiments shown, but isto be accorded to the widest scope consistent with the principles andfeatures disclosed herein.

Shown in FIG. 4 is a block diagram example of a system to implementautomated tubing connections utilizing a receiving hardware andcompression system 10 and a plurality of “plug and play” insert devices11 that will be subsequently compressed resulting in automated seals forthe processing of fluid streams. Fluid, gas or liquid, may be providedby a fluid delivery system 12 integrated with the receiving hardware 10.The resulting transferred or processed fluid may then be delivered tofluid processing hardware or a detector system 13. The inserts 11contain the necessary structures such as ferrules, receiving ports andmaterials necessary to seal the tubing and fluidic components to thereceiving hardware 10. The inserts 11 may contain one more componentsfor fluid processing and manipulation. Furthermore a plurality ofinserts, present in either a serial or parallel fashion, may exist asshown in FIG. 32.

Shown in FIG. 5 is a block diagram example of a system to implementautomated pressure connections utilizing a receiving hardware andcompression system 10 and the “plug and play” sample/analyte containingat least one insert 14. In this embodiment the sample/analyte containinginsert 14 is interfaced via the receiving hardware and compressionsystem 10 and the sample/analyte contained in the insert may besubsequently processed by the fluid processing hardware or detectorsystem 13. The sample/analyte contained in the insert may be manipulatedby pressure such as a pumping mechanism, vacuum, positive displacement,negative displacement, capillary force, pumping systems or the like. Thesample/analyte containing inserts may be either disposable or reusable.The system may further operate as an autosampler injector system inconjunction with other fluid processing hardware or detector systems.When the insert is used only once, sample-to-sample cross-contaminationis not possible as the sample/analyte is only exposed to thesample/analyte insert a single time. When the device is used only once,there is no risk of carry-over, leading to faster cycle times betweensample analyses as there is no need for a washing cycle between samples.The insert is loaded with sample in a manual or automated fashion viapositive or negative displacement. The sample loading or collection mayoccur either locally or remotely as part of a sampling system. In oneembodiment the autosampler loads the sample into a high pressuresampling port having a compression connection of the present invention.

Shown in FIG. 6 is across-sectional view of an automated compressionsystem and fitting components capable of making automated high and lowpressure fluidic connections. The drive force compression hardware 30supplies axial-directed driving force to the ferrule 31. The axial forcecompresses the tapered ferrule 31 against the tapered receiver port 32,which in turn effects a seal by creating a singular plane of contactaround the circumference of the tube 33. The outer surface of theferrule 31 and the inner surface of the receiver port 32 are bothsubstantially smooth. The driving force mechanism may be applied byhuman intervention, or preferably, in an automated fashion by any devicesufficient to provide a driving force such as, but not limited to, amechanical lead screw, servo motor, pneumatic components, mechanicalcomponents, hydraulic components, spring mechanisms, or the like. Thedrive force does not cause rotational torque on the ferrule 31, receiverport 32, or tube 33. The drive force is controlled by a forcemeasurement system in communication with the force measurement sensor34. The receiving port 32 is supported by mechanical support structures35 to prevent movement of the receiving port 32. The applied compressionforce is axial in nature and does not cause twisting or rotating of theferrule or tube, thereby eliminating the risk of damaging the fragiletubing ends by grinding them against surfaces with which they come incontact. The driving force is measured by the force measurement sensor34 that results in the accurate and precise readings of the drivingforce and ultimately the compression force applied. The force drivesystem is the system that receives force feedback from the forcemeasurement sensor 34 and adjusts the force compression hardware 30 toexert the proper force on the compression system. The system allows foraccurate and precise control of the fitting compression. The appliedcompression forces can be either static (fixed) or dynamic(programmable) to change the compression force over time as needed toform a proper sealing force. This accurate and precise control of boththe drive mechanism and the force measurement eliminates the possibilityof over compressing the fitting, which could cause leaking, cracking,and particle generation problems. The force measurement sensor can be amechanical strain gage, piezoelectric sensor, transducer, load cellsensor, or resistance sensor. Additionally, the force measurement sensorcan measure the direct or indirect force.

For a cylinder-based drive force systems, the applied force can becalculated indirectly by using the applied gas or hydraulic pressure andthe cylinder diameter. The fluid pressure applied to the cylinder may bemeasured with an analogue or digital pressure sensor.

For a geared drive force system, such as a servo motor or a lead screw,the drive force may be indirectly determined by using the applied torquefrom the motor and the gearing parameters. Additionally a torque sensormay be placed in-line.

Direct measurement for any drive system may determined by placing ananalogue or digital sensor in-line between the drive mechanism and thesubstrates to be compressed, such as an analog strain gage, a digitalstrain gage, or preferably, a load cell. The gage or load cell may bechosen for a given application range to provide an accurate and preciseapplied force measurement. The gage or load cell could also be presentin a system to provide feedback for changing the applied force by thedrive force measurement.

The connecting and fitting materials may be made of conductive,insulator, or doped materials including metals, metal mixtures oralloys, glass, ceramic, metal-semiconductor mixtures or alloys,polymers, conductive polymers, carbon or graphite, mixtures of carbonand polymers or plastics, organic compounds, elastomers, fluoropolymer,monomers, waxes, mixtures of inorganic-organic compounds and anycombination thereof It is understood that although the seal has beendescribed as being made by a ferrule to receiver port connection,variations of the invention include compressing and sealing by cone,port-based, flatbottom, flanged, flangeless, or alike fitting ferrulecombinations. The fittings can be of any shape or configuration and mayinclude be part of an auxiliary device such as, but is not limited to,one or more inlets, outlets, transfer lines, traps, electrosprayemitters, filters, frits, reactors, unions, tees, manifolds, mixers,vessels, injectors, adapters, backpressure regulators, couplers, plugs,loops, needles, columns, pre-columns, nano-liquid chromatographycolumns, injector valves, check valves, metering valves, splittingvalves, purge valves, switching valves, needles, Y-connecters, or otherlike fluidic components.

The connecters and fittings may be used in isolation or as part of asystem. The fittings can be integrated into a hardware device or act asfree standing connections.

Shown in FIGS. 7A and 7B is across-sectional view of an automatedcompression system and fitting components capable of making multiple,automated, high and low pressure fluidic connections. As shown in FIG.7A, two separate tubes, 42 and 43, in communication with a dual-sidedreceiving port 41 are sealed via axial force generated by a singledriving force compression system 44 with a mechanical support 45preventing the movement of ferrule 47. The drive forces are controlledby the force drive system. As there is only a single drive forcemechanism, both tubes 42 and 43 are sealed with equal compression force.All fittings in the axial plane of and between the single driving forcecompression system 44 the mechanical support 45 are compressed with thesame force. The dual-sided receiving port 41 can move or “float” untileach fitting is compressed or loaded against the mechanical supports 45.Thus altering the applied drive force would influence the compressionforce applied to all of the in-line components. It is understood thatmultiple drive forces can be existed on the system to effect a seal.

Referring to FIG. 7B, there is shown an alternative embodiment with twoseparate tubes 42 and 43 in communication with a dual-sided receivingport 41 are sealed via axial force generated by a dual driving forcecompression system 46 with mechanical support 45 preventing the movementof the dual-sided receiving port 41. The drive forces are controlled bythe force drive system. The dual-sided receiving port 41 is fixed inplace by mechanical supports 45. Thus, the compression force applied tothe fittings and tubes on each side of the receiver port can beindependently controlled. This allows for compression to be appliedindependently to a specific fitting, which can be incorporated into alarger array or a plurality of fittings. This independence allows forindividual components within a system to be compressed and releasedsolitarily, allowing for automated changing of specific componentswithout changing the compression of other fittings.

Referring to FIG. 8A, there is shown across-section of an insertcontaining multiple components including: ferrules 31, receiver ports51, capillary tubes 52, and a floating mechanical structure 53 in theinsert housing 54. Ferrules, receiver ports, and fitting components areintegrated within the internal structure of the insert. Once the insertis placed in the receiving hardware, a single driving force compressionsystem 44 is applied to one end of the insert while the opposing insertend is constrained by mechanical supports 45. The compression forcegenerated in this manner is transferred to all components, ferrules, andreceiving ports present in the array, as the insert contains a floatingstructure which transfers force to all components within the insert. Inthis manner, sealing of multiple tubes within the insert is achieved,using a single axial drive force. The floating mechanical structure 53allows components to be separated or located in distinct regions of thearray. It is understood that although a linear structure is shown, otheroff-axis geometries are applicable. The drive force is controlled by theforce drive system.

Referring to FIG. 8B, there is shown a cross-section of an insertcontaining multiple components: including: ferrules 31, receiver ports51, capillary tubes 52, and a fixed mechanical support 55 in the inserthousing 54. Ferrules, receiver ports, and fitting components areintegrated within the internal structure of the insert. The insert alsocontains a structure that is a fixed mechanical support 55 which remainsstationary when force is applied by the dual driving force compressionsystem 46. Once the insert is placed in the receiving hardware, twoindependently operated axial drive forces are applied to each end of theinsert. The component fittings, ferrules, and receiver ports arecompressed against the fixed mechanical support 55 contained within theinsert. Fittings on either side of the fixed mechanical support may becompressed and sealed with independent force as applied by each driveforce mechanism of the dual driving force compression system 46. Sealingof multiple tubes within the insert is achieved. The fixed mechanicalsupport 55 may be affixed to the insert itself or may be locked in placerelative to the receiving hardware. It is understood that although alinear structure is shown, other off-axis geometries are applicable. Thedrive force is controlled by the force drive system.

Referring to FIG. 9A, there is shown a cross-sectional view of anassembly of component fittings, where the insert 60 houses only some ofthe components, and a single driving force compression system 44 isemployed to generate the compression sealing force both internally andexternally to the insert 60. Integrated within the insert are ferrules61, tubes 62, and the floating mechanical structure 53. External to theinsert and part of the receiving hardware are ferrules 31, receivingports 51, and tubes 52. Once the insert is placed in the receivinghardware, the single driving force compression system 44 applies drivingforce to one end of the assembly, while the opposing end is constrainedby mechanical supports 45. The compression force generated in thismanner is transferred to all in-line fitting components containedbetween the single driving force compression system 44 and themechanical supports 45. It is understood that the insert can contain anynumber of tubes, columns, reactors, or any other device desirable inchromatographic and fluidic applications.

Referring to FIG. 9B, there is shown is a cross-sectional view of anassembly of component fittings, where the insert 60 houses only some ofthe components, and the dual driving force compression system 46 isemployed to generate the compression sealing force both internally andexternally to the insert 60. Integrated within the insert are ferrules61, tubes 62, and the fixed mechanical support 55. External to theinsert and part of the receiving hardware are ferrules 31, receivingports 51, and tubes 52. Once the insert is placed in the receivinghardware, the dual driving force compression system 46 applies axialforce independently. to each end of the component assembly. Thecomponent fittings, ferrules, and receiver ports are compressed againstthe fixed mechanical support 55 contained within the insert. Fittings oneither side of the fixed mechanical support 55 may be compressed andsealed with independent force as applied by each end of the dual drivingforce compression system 46. The fixed mechanical support 55 may beaffixed to the insert itself or may be locked in place relative to thereceiving hardware. It is understood that the insert can contain anynumber of tubes, columns, reactors, or any other device desirable inchromatographic and fluidic applications.

Shown in FIG. 10A is a cross-sectional view similar to FIG. 9A of anassembly of component fittings, where the insert 60 houses only some ofthe components, and a single driving force compression system 44 isemployed to generate the compression sealing force both internally andexternally to the insert 60. In one embodiment the insert houses acolumn and a spray emitter.

Shown in FIG. 10B is a cross-sectional view similar to FIG. 9B of anassembly of component fittings, where the insert 60 houses only some ofthe components, and a dual driving force compression system 46 isemployed to generate the compression sealing force both internally andexternally to the insert 60. In one embodiment the insert houses acolumn and a spray emitter.

Shown in FIG. 10C is a cross-sectional view of a fitting assembly. Theassembly contains a plurality of inserts 60 in-line with the drivingforce. The compression force is transferred to all in-line fittingcomponents. It is understood that any number of inserts may be linkedtogether and any number of fittings may be placed between inserts.Although a single driving force compression system is shown it isfurther understood that a dual driving force compression system may beused without departing from the scope of the invention. In oneembodiment each insert contains a single tube, pre-column, column,reactor, spray emitter, or other device desirable in chromatographic andfluidic applications. It is understood that many inserts can be sealed,end-to-end, in a tandem fashion.

Shown in FIG. 11 is a cross-sectional view of an automated compressionsystem and fitting components capable of making automated high and lowpressure fluidic connections. The driving force compression hardware 80supplies radial directed driving force relative to the ferrule 82 andreceiving port 83. An angled, clamping structure 81 pushes and squeezesthe outer edges of the ferrule 82 and receiving port 83, subsequentlygenerating axial directed force. The translated axial force compressesthe tapered ferrule 82 against the tapered receiver port 83, which inturn affects a seal by creating a singular plane of contact around thecircumference of the tube 84. A mechanical support structure 86 preventsmovement of one of the clamping structures 81. The drive force iscontrolled by a force measurement system in communication with the forcemeasurement sensor 85. The applied compression force is axial in natureand does not cause twisting or rotating of the ferrule or tube, therebyeliminating the risk of damaging the fragile tubing ends by grindingthem against surfaces with which they come in contact. The driving forceis measured by the force measurement sensor 85 which results in accurateand precise readings of the driving force and ultimately the compressionforce applied. The drive force system is an automated system withfeedback from the force measurement sensor 85 controlling the driveforce compression hardware 80. The system allows for accurate andprecise control of the fitting compression. The applied compressionforces can be either static (fixed) or dynamic (programmable) to changethe compression force over time as needed to form a proper sealingforce. This accurate and precise control of both the drive mechanism andthe force measurement eliminates the possibility of over compressing thefitting, which could cause leaking, cracking, and particle generationproblems. It is understood that a drive force may be applied to eachclamping element. It is further understood that the clamping elementsmay take any shape capable of generating an axial compressing force, andthe clamping elements may be of differing shapes.

Shown in FIGS. 12 and 13 are cross-sectional views of automatedcompression systems and fitting components capable of making multiple,automated, high and low pressure fluidic connections. FIGS. 12 and 13show a dual-sided receiving port 87 where two separate tubes 88 and 89,are sealed via radial drive force movement, and this movement issubsequently converted to axial force generated by a driving forcecompression system 90. The drive force is controlled by the force drivesystem.

Referring to FIG. 12, both tubes 88 and 89 are sealed with equalcompression force as there is only a single drive force employed. Thedrive force is generated in the radial plane which is then mechanicallyconverted to axial directed force by an angled, clamping structure 81which pushes and squeezes the outer edges of the ferrule 82 andreceiving port 87. All fittings between the angled clamping structuresare compressed, thus a plurality of seals may be made by the singledrive force mechanism. Altering the applied drive force changes thecompression force applied to all of the components contained within theangled, clamping structure 81.

Referring to FIG. 13, tubes 88 and 89 are sealed using two independentclamping elements 81. Each side of the two-sided receiving port 87 hasan independent drive force with a corresponding angled, clampingstructure 81 and a ferrule 82. Each clamping element 81 mayindependently push and squeeze the outer edges of the correspondingferrule 82 and receiving port 87, subsequently generating axial directedforce. The application of two distinct drive forces and two clampingelements allows for the compression force applied to the fittings andtubes on each side of the receiver port to be independently controlled.This allows for compression to be applied independently to specificfittings which are incorporated in a larger array or a plurality offittings. This independence would allow for individual components withina system to be compressed and released solitarily, allowing forautomated changing of specific components.

Referring to FIG. 14, there is shown a cross-sectional view of anassembly of fittings present in an insert. Ferrules 82, receiving ports87, tubes 84, clamping structures 81, and structural housing 110 are allcontained in the insert. Here a single drive force applies radial forceto the rigid structural housing 110 of the insert. This radial driveforce in turn pushes two angled, clamping structures 81 which convertthe radial drive force applied into axial force. Here a single radialdrive force is applied to two angled, clamping structures, however asingle radial drive force could be applied to many angled, clampingstructures, making many compression connection seals.

Shown in FIG. 15 is a cross-sectional view of an assembly of fittingspresent in an insert. Ferrules 82, receiving ports 87, tubes 84,clamping structures 81, and structural housing 110 are all contained inthe insert. Here two drive force mechanisms apply radial force to therigid housing structure of the insert. Each radial drive force in turnpushes a corresponding angled, clamping structure which converts theradial drive force applied into axial force. Each radial drive force isoperated independently which allows the axial compression forcegenerated by each clamping structure 81 to be independently controlled.Each radial drive force mechanism and its corresponding clampingstructure are shown to make two seals. In a similar manner, if theangled, clamping structure only spanned a ferrule and receiving port (asshown in FIG. 16) then single seals could be independently controlled.Although radial drive force mechanisms are shown on both sides of theinsert housing it is understood that drive force mechanisms could bepresent on a single side and push against mechanical supports oppositethem as both embodiments allow for a radial, squeezing force to begenerated.

FIG. 16 is a cross-sectional view of an assembly of fittings, some ofwhich are present in the insert. Ferrules 82, receiving ports 87, tubes84, clamping structures 81, and structural housing 110 are all containedin the insert. External to the insert are additional ferrules, receivingports, and tubes. A plurality of drive forces apply radial forces. Tworadial drive forces are directly applied to clamping structures 81exterior to the insert. In both cases the angled, clamping structureconverts the radial drive force into axial force which generates acompression seal. Here each drive force external to the insert makes asingle compression seal. If the clamping structures spanned more than asingle fitting, more seals could be made by a single drive force. Athird drive force applies radial force to the rigid housing 110 of theinsert. The insert contains multiple clamping structures 81 so whenradial force is applied by the drive force mechanism, the force isapplied all along the rigid insert housing and subsequently is appliedto the multiple angled, clamping structures. The angled, clampingstructures convert the radial force to an axial force, which in turncreates compression seals between the fitting components.

Shown in FIG. 17A is a cross-sectional view of a three-channel connectoremploying the “plug-and-play” system having female receiving portconnector ends 140 for interfacing with three corresponding ferrules.Alternatively, shown in FIG. 17B, the three-channel connector havingmale ferrule connector ends 141 for interfacing with three correspondingreceiver ports 142. In both embodiments, each correspondingferrule/receiving port union at each channel is individually compressedby an axial driving force compression system 143. This force can beapplied by either individual drive force mechanisms or by a singlesystem that addresses the three channels. The three channel structuremay act as a tee, mixer, manifold, or reactor.

Shown in FIG. 18 is a cross-sectional view of a four-channel structurehaving male ferrule connector ends 150 for interfacing with fourcorresponding receiver ports 151. Alternatively, the connector endscould be female receiving port ends and interface to ferrules or acombination of male ferrule and female receiving port ends. The“plug-and-play” technology is employed to make the connections of theports. Each ferrule/receiving port union at each channel is compressedusing axial drive force movement. This force can be applied byindividual drive force compression systems or by a single system thataddresses all the four channels. The four channel structure may act as atee, union, mixer, manifold, or reactor. It is understood thatstructures with additional channels can be employed.

In an alternative embodiment the “plug-and-play” compression fittingconnection is used to connect any type of tube or fluidic component to aconventional multi-port valve used to redirect fluid streams. Thesevalves are commonly referred to as switching valves. Compression fittingconnections are made to one or more of the valve ports. A port on theswitching valve serves as the receiver port in the compressionconnection. The valve is fixed to the docking station via a mechanicalsupport. There are corresponding drive force systems for each port ofthe switching valve having a compression fitting connection.Alternatively the valve is mounted to traditional hardware and has anintegrated force drive system.

Referring to FIGS. 19A and 19B, there are shown cross-sectional views offluid (gas or liquid) containing vessels where the fluid is a targetsample of interest. The vessel is pre-filled with a sample, analyte,reactant, etc. and is then interfaced to an analysis system using“plug-and-play” technology. Delivery of the fluid sample to the analysissystem may be via displacement using positive or negative pressure.

Shown in FIG. 19A is a cross-sectional view of a single orifice vessel160 having a ferrule 161 around the opening which can seal against areceiver port 162 system by axial drive force movement. The vessel 160may contain a target sample of interest that can be manipulated withpositive or negative pressure.

Shown in FIG. 19B is a cross-sectional view of a multi-orifice vessel163 having ferrules 161 around each of the openings which can sealagainst receiver ports 162 when axial force is generated by a controlledaxial drive force movement. The vessel may contain a target sample ofinterest that can be manipulated with positive or negative pressure.

A gaseous target sample is collected into a sample vessel from anexternal system that either injects the vessel with sample, or pullssample into the vessel using a vacuum. For example, the vessel couldcontain one or more ports (not shown), in addition to the one or moreentrances or exits. The ports and entrance/exit openings may containcheck valves, septa, or plugs to constrain/seal the gas in the vessel. Apump may be connected to one such port, applying vacuum to the vesseland thereby pulling gaseous sample into the vessel through an additionalopen port.

In an alternative embodiment, the vessel is pre-evacuated prior to use.At the time of sample collection, the vessel port is opened via a valveor alternatively pierced, if designed with a septum-like mechanism. Thegaseous sample is pulled into the vessel due to the pressuredifferential. Once the sample has been collected, the entry/samplingport is either closed in the case of the valve, or re-sealed in the caseof the septum.

In one embodiment the vessel acts as a simple storage vessel, orcontains a material for trapping desired components, or analytes. Thetrapping material may be metal, plastic/polymeric, ceramic, solid phaseextraction material, chromatographic media, particle, monolith, or amembrane support structure. The vessel also acts to store and protectthe sample from the environment until its use. The vessel may beinsulated or thermally conductive if maintaining constant temperature isdesired. The gaseous sample is pulled or swept by the trapping material,which is integrated in the insert, during sample collection. Once thesampling has occurred, the vessel insert is placed into the receivinghardware. Compression connections are made prior to sample processingand analysis. The gaseous sample and/or the trapped sample componentsare delivered to the gas processing hardware or detector, such as a gaschromatograph, ion mobility instrument, or mass spectrometer. The sampledelivery is achieved by pressurizing the vessel, or by evacuating thevessel. This is accomplished by a separate port or a common port withmultiple access openings.

In an alternative embodiment, the vessel is also heated to releasetrapped components on the trapping structure integrated in the vessel.Alternatively, the trapping structure is removed from the vessel andplaced in a different plug-and-play insert with additional components.

The plug-and-play vessel allows for automated sampling of gases. Asampling robot first “loads” the vessel, and then the vessel istransferred to processing hardware. The plug-and-play system isinterfaced to this processing/detector hardware. The vessel insert isplaced into the receiving hardware, the compression connections aremade, and then the sample within the vessel is transferred to theprocessing/detector hardware in an automated fashion. In one embodimentthe vessels are used in remote sampling applications, such as forchemical detection applications. Subsequently samples are collected intothe insert vessels at a location remote from the receiving hardware andfluid processing equipment.

Liquid samples are collected into a sample vessel with two openings, asshown in FIG. 19B. The vessel is introduced to the target sample ofinterest in a perpendicular fashion such that one opening of the vesselis submerged in liquid sample of interest. The liquid sample enters thevessel, either by capillary action or by applying negative pressure tothe end of the vessel not submerged in liquid sample, drawing the sampleup into the vessel. The vessel is then placed into the “plug-and-play”compression system, and connections are made as indicated in FIG. 19B. Aliquid stream from an LC pump or positive pressure source, expels thetarget sample of interest from the vessel itself. The vessel having thecompression fittings are designed to contain features allowing forrobotic handling and manipulation. The vessels can either be re-usableor used as a one-time-use disposable item. For disposable vessels, onlya single sample comes into contact with each vessel allowing for nosample-to-sample carryover or cross-contamination.

It is understood that both the gaseous or liquid sample vessel insertsmay also contain columns, fits, filters, solid phase extraction, andreaction media.

Shown in FIG. 20 is an insert containing an integrated optical portchannel 170. When the insert 100 is placed into the receiving hardwarethe light path generated from the light source 171, traverses theoptical port channel 170 in the insert, and is in alignment with thedetector 172. After alignment sample or analyte traveling through thetube or column can be detected by such techniques as visible,ultra-violet (UV), infrared, absorbance, transmission, or fluorescence.It is understood that the insert can contain a single or plurality ofoptical channels. In an alternative embodiment the optical channelthrough the insert is used to expose the sample or analyte to an energysource.

Referring to FIG. 21, there is shown an insert 100 with electrodes 180integrated into the insert 100. The insert 100 is placed into thereceiving hardware and the electrodes 180 integrated in the insert 100make contact with corresponding pads in the receiving hardware. Theelectrodes can perform electrochemical oxidation/reduction reactions,measure conductivity, pH, etc. Alternatively, the electrodes 180 canapply the electric potential needed to conduct capillary electrophoresis(CE), capillary electrochromatography (CEC), isoelectric focusing, orsimilar electric field applications. Additionally, the electrodes 180can serve as a catalyst for on-line reactions.

Referring to FIG. 22, there is shown a fitting assembly with leaksensors 190 located in close proximity to the seal and compressioninterface. The contact electrodes are in close proximity to the fluidseal junction where leaks are most likely to develop. In one embodimentthe sensor is located within 500 μm of the leak resistant seal When aleak develops the fluid 191 comes into contact with the sensor material192. The sensor may detect the leak by resistance, change in potential,reaction, voltage detection, current detection, circuit closure, etc.For leaks of small liquid volumes, as one would expect from techniquessuch as nanoLC, CE, CEC, etc., it is important the sensors are locatedin close proximity to the leak as evaporation prevents significantliquid build-up. A plurality of leak sensors can be positioned in manylocations throughout a fitting assembly to isolate and diagnosecomponent failure and system issues. The leak sensors are capable ofdetecting leaks of less than 1 mL/min. In one embodiment the leaksensors are capable of detecting leaks of less than 1000 nL/min. In anadditional embodiment the leak sensors are capable of detection leaks ofless than 20 nL/min. In one embodiment the leak sensor is disposed inthe receiving port or ferrule. In an alternative embodiment the leaksensor is positioned between the receiving port and the ferrule.

In one embodiment of the present invention, an electrode is used todetect leaks. The electrode materials may include metals, metal mixturesor alloys, metal-semiconductor mixtures or alloys, conductive polymers,carbon, graphite, mixtures of carbon and polymers, plastics, or anycombination thereof The electrode can be of any shape. The electrodesurface may be smooth or rough. The electrode surface are placed in thesystem where leak detection is desirable such as, but not limited to,integrated into the system via the connections themselves, in closeproximity to the tubing, or through devices such as contact pads,clamps, sleeves, or wires. The sensor can be in the form of wire,contact pads, conductive materials or doped-materials. Examples include,but are not limited to, conductive collars, wires, contact pads,sleeves, or embedded electrodes placed in the desired zone fordetection.

According to one aspect of this invention, the leak sensors is coatedwith alternative materials by dipping electrodes into a coating solutionor deposited by gas phase deposition. In one embodiment the leak sensoris made of a conducting material that is deposited, evaporated,puttered, dip-coated, electroplated, electo-coated, or doped. Thecoating of an electrode is made by polymeric or other organic materialgrowth in solution or in gas phase. In an alternative embodiment theleak sensor is glass, metal, plastic, polymer, alloy or doped material.In one embodiment the sensor is designed to be inert so to limitinteractions or incompatibility with the sample or solution. The sensorsurface area can be of various sizes and/or surface areas. In oneembodiment the sensor is fully integrated within the device, includingintegration of processing and monitoring and control electronics. Thesensor can either be a detector or send signals to a component orsystem. The processing, monitoring and control electronics are locatedoff the device and the sensor only contains the detection component.Alternatively, the processing, monitoring and control electronics areintegrated within the sensor. The sensor is connected to electronics viaphysical connections such as wires or conductive material connections ormay communicate through wireless connections to remote electronics viaradio frequency, infrared, blue tooth, RFID or other wireless formats.

Shown in FIG. 23 is a “plug-and-play” compression fitting with contactleak sensors 200 positioned external to the outer fitting surfaces. Asliquid leaks from the fitting, it fills the inner void of the fittingand the fluid will begin to protrude and touch the sensor. In oneembodiment the fitting has a structure that helps to wick the fluid tothe sensor or to a location in the insert where a sensor isstrategically located. The connection can be coated with a hydrophilicsurface or may use capillary action to deliver leaking liquid to thesensor. In one embodiment the sensor is located within 25,000 μm of theleak-resistant seal. In one embodiment the a narrow channel with a widthof less than 500 μm is used to create the capillary action. In analternative embodiment the narrow channel is less than 250 μm. Aplurality of these sensors can be positioned in many locationsthroughout a fitting assembly to isolate and diagnose component failureand system issues. The leak sensors are capable of detecting leaks ofless than 1 mL/min. In one embodiment the leak sensors are capable ofdetecting leaks of less than 1000 nL/min. In an additional embodimentthe leak sensors are capable of detection leaks of less than 20 nL/min.Additionally, the leak sensor can be an electronic leak sensor capableof detecting conductivity, current, voltage, resistance, or change inelectrical potential.

Shown in FIG. 24 is a “plug-and-play” fitting with non-contactoptical-based leak sensors. The optical, light-based sensor uses lighttransmitted through an opening or passage within the fitting geometry. Alight sensor 211 is aligned opposite the light source 212 in the lightpath so that it can measure the amount of transmitted light. Lightsources include UV, visible, infrared, and laser-based. The opticalsensor is capable of detecting light transmission, reflectance,absorbance, refractive indexes, and spectral changes. In an alternativeembodiment the light sensors detect additional light measurementsinclude refractive index, absorbance, and spectral changes. A pluralityof sensors can be positioned in many locations throughout a fittingassembly to isolate and diagnose component failure and system issues.The leak sensors are capable of detecting leaks of less than 1 mL/min.In one embodiment the leak sensors are capable of detecting leaks ofless than 1000 nL/min. In an additional embodiment the leak sensors arecapable of detection leaks of less than 20 nL/min.

Referring to FIG. 25, there is shown a “plug-and-play” fitting withnon-contact optical-based leak sensors. The optical, light-based sensoruses transmitted light to detect liquid that has leaked external to thefitting. An optical source 220 is positioned to send light adjacent tothe outer surface of the fitting, and the sensor 221 is placed inalignment with the light path. As liquid leaks from the fitting, thechange in transmitted light is measured. Light sources include UV,visible, infrared, and laser-based. In one embodiment the sensor iscapable of measuring refractive index, absorbance, or spectral changesto detect leaks. A plurality of these sensors can be positioned in manylocations throughout a fitting assembly to isolate and diagnosecomponent failure and system issues. The leak sensors are capable ofdetecting leaks of less than 1 mL/min. In one embodiment the leaksensors are capable of detecting leaks of less than 1000 nL/min. In anadditional embodiment the leak sensors are capable of detection leaks ofless than 20 nL/min.

Shown in FIG. 26 is a “plug-and play” fitting with non-contactoptical-based leak sensors utilizing reflected light from internalregions of the fitting. An optical source 230 is positioned to sendlight to open paths into the fitting, and reflected light is measured.If a leak develops, liquid in the light path will result in a change inthe amount of reflected light read by the sensor 230. Light sourcesinclude UV, visible, infrared, and laser-based. A plurality of thesesensors can be positioned in many locations throughout a fittingassembly to isolate and diagnose component failure and system issues.The leak sensors are capable of detecting leaks of less than 1 mL/min.In one embodiment the leak sensors are capable of detecting leaks ofless than 1000 nL/min. In an additional embodiment the leak sensors arecapable of detection leaks of less than 20 nL/min.

Shown in FIG. 27 is a “plug-and-play” fitting with a non-contactoptical-based sensor for detecting reflected light external to thefitting. An optical source 240 is positioned so that light reflectingexternal to the fitting can be measured. In the event that fluid leaksfrom the fitting and protrudes from or wets the external surfaces of thefitting, the sensor 240 detects a change in reflectance. Light sourcesinclude UV, visible, infrared, and laser-based.

A plurality of these sensors can be positioned in many locationsthroughout a fitting assembly to isolate and diagnose component failureand system issues. The leak sensors are capable of detecting leaks ofless than 1 m/min L. In one embodiment the leak sensors are capable ofdetecting leaks of less than 1000 nL/min. In an additional embodimentthe leak sensors are capable of detection leaks of less than 20 nL/min.

Referring to FIG. 28, there is shown an embodiment of a “plug-and-play”nanoliquid chromatography and nanoelectrospray insert, and its receivinghardware. The insert 250 contains the “plug-and-play” ferrule 251, andthe receiving hardware 252 contains the ferrule's correspondingreceiving port 253. In one embodiment the insert 250 contains ananoliquid chromatography capillary column, nanoelectrospray emitter,protective sheath 254 to protect the spray emitter, and integrateddiagnostic leak and nanoelectrospray sensors (whose electricalinterconnects are not shown). The receiving hardware 252 ensures thatthe insert 250 is accurately positioned in front of the detector (notshown) to yield optimal results.

The insert 250 or the retractable sheath 254 can provide gas deliveryfor nebulization, auxiliary fluid, drying gases, curtain gas, or forchange in gaseous atmosphere. In one embodiment the sheath 254 is madeof a conductive or partially conductive material to provide otherfunctionality where varying electrical potentials are applied forattributes such as electrical gate or field free region. The sheath canalso act as the spray sensing device or electrode.

An insert 250 is placed into the receiving hardware 252 where one ormore leak sensors are either integrated into or around the receiver port253 or tube inlet ferrule 251. The sensors can be in the insert 250 andconnected via electrical connection to the receiving hardware 252 or thesensors may be part of the receiving hardware 252 and in an appropriateposition to detect liquid leaking. The sensors can be integrated,mechanically fixed, or casted into place. In an alternative embodiment,the insert contains sensors capable of measuring fluid flow rate, fluidpressure, fluid backpressure, electrical current, electrical voltage,electric field strength, electrospray current, gas velocity, gaspressure, fluid density temperature, absorbance, light transmission,reflectance, chemical detection, and optical detection.

In one embodiment, the insert 250 contains an electrospray emitterprotected by a retractable sheath 254. Upon manual or automatedplacement of the insert 250, the connector is compressed via thecompression fitting hardware the high pressure connection is made. Thecompression can be achieved by either manual intervention or viaautomation.

The receiving hardware 252 station can accept one or more inserts 250and has manual or automated translational stages for aligning the insert250 to a detector or to fluid processing instrumentation. Furthermore,the receiving hardware 252 can be adapted to use one or more inserts 250in a serial or parallel fashion. In one embodiment the receivinghardware 252 has integrated electronics or interconnects for interfacingto the devices within the insert 250. The receiving hardware 252 allowsfor a means of interfacing the packaged device to detectors such as amass spectrometer. The detector type may be of any type suitable forfluid processing.

The invention could also be used to perform on-line synthetic chemistryand to study on-line synthetic chemistry reaction kinetics. Reactantsand analytes are injected into the fluid stream. Inserts containingintegrated optical port channels, with a light source and detectormonitor the reaction kinetics. Alternatively a detector external to the“plug-and-play” system, such as a mass spectrometer or UV detectorreceives the fluid stream and monitors the reaction kinetics.Alternatively, the insert contains an integrated, catalytic electrodesor light sources to perform reaction chemistry. With conventionalflow-through reactor chemistry, the formation of reaction products thatare not soluble and precipitate within the reactor is a major concern,due to clogging issues. The present invention allows for an in-linefilter insert that can be replaced periodically in an automated fashionthroughout the duration of the reaction and experiment. A time intervalfor component switching or alternatively, pressure and flow sensors isused to determine the appropriate time to change the filter or reactionchamber. The insert can contain an alignment device to ensure properalignment in the docking hardware such as a physical protrusion, hollowchannel, or optical sensing devices.

Shown in FIG. 29A is an expanded view of the insert 250 in the receivinghardware 252 where the ferrule 251 and receiver port 253 are not sealedby the drive force compression mechanism 255.

Referring to FIG. 29B, there is shown the same expanded view as in FIG.29A with the axial drive force applied by the compression mechanism 255to the receiving port 253, sealing the column. The receiving port isaffixed to the drive force mechanism which is built into the receivinghardware. Upon manual or automated placement of the insert 250 into thereceiver hardware 252, the high pressure connection is made. This axialdrive force results in the receiving port engaging and compressing theferrule onto the capillary nanoliquid chromatography column inlet. Thisseal has none of the negative attributes of conventional torque fittingsthat rotate and twist ferrules and capillary columns. The forcemeasurement sensor 256 provides monitoring and control for accurate,precise, and reproducible sealing forces. The drive force can be a leadscrew, motor servo motor, pressure system, pneumatic device, hydraulicdevice, magnet or spring. In an alternative embodiment, the drive forcecompression mechanism can compress a plurality of compression fittingsin series or parallel. In an alternative embodiment, a plurality ofdrive force mechanisms are used to compress a plurality of compressionfittings in series or parallel.

Shown in FIG. 29C is the x-ray view of FIG. 29B showing the insert inthe receiving hardware with the compression seal made between theferrule 251 from the insert 250 and the receiving port 253 from thereceiving hardware. The leak sensor electrode 257, at the compressionconnection with its interconnect contact pad 258 at the base of theinsert is shown. The nanoliquid chromatography column 259, which isimbedded in the insert 250, is also shown. It is understood thatalthough the invention has been shown as compressing the ferrule on thetube an alternative embodiment includes the use of a sleeve placed overthe tube such that the ferrule is compressed by the receiver port, theferrule compresses on the sleeve and subsequently, the sleeve compresseson the tube. Sleeves can act as an interface allowing the use offerrules of a single size to seal various sized tubing.

Referring to FIG. 30A, there is shown a cross-sectional view with theinsert 250 placed in the receiving hardware 252 and the sheath 254retracted exposing the spray emitter 260. The nanoLC column 259, sprayemitter 260 and diagnostic sensors, all of which are imbedded in theinsert, are shown. At this point the system is ready to perform sampleanalyses. As shown in this embodiment two diagnostic leak sensors areintegrated into the insert, one for detecting leaks at the column inletseal 262, and a second 261 for monitoring leaks at the column-to-emitterinterface connection 263. Also shown is the electrospray diagnosticsensor 264 which monitors the spray current when in operation.

Shown in FIG. 30B is the insert 250 placed in the receiving hardware252, the compression connection made, and the sheath 254 retractedexposing the spray emitter 260. The receiving hardware would beconnected to electronics and a data system for sensor monitoring andsystem control.

Referring to FIG. 31, there is illustrated system integration. The datasystem collects feedback from the sensors, performs roboticmanipulation, and manages communication input and output. Externalcommunication input and output could be wire or wireless via internet,phone, RF, or Bluetooth.

In one embodiment the liquid chromatography electrospray system has oneor more sensors that include liquid detection, liquid flow rate, fluidpressure, fluid backpressure, electrical current, electrical voltage,electric field strength, electrospray current, gas velocity, gaspressure, fluid density temperature, absorbance, light transmission,chemical detection, and optical detection.

The placement of the sensors may be invasive or non-invasive in nature.The sensors may be part of the chromatography wall surface viaembedding, or as part of the actual structure, or as part of the fittingcomponents. Alternatively the sensors may be located in varyingproximity to the desired monitoring region, in either the insert orreceiving hardware. According to one embodiment of this invention, theelectrospray sensors may detect spray current, electric field strength,droplet size. The electrospray sensors may stand alone, be integratedwith the consumable components, the insert, or be part of a massspectrometer system.

The system has ability to self-diagnose certain system malfunctionsincluding, but not limited to liquid or gas leaks, and changes inelectrical potentials, backpressure, column pressure, optical spectrum,electrochemistry, electrospray current, chromatographic performance, andthose alike.

When the sensors indicate the system is malfunctioning, the datamonitoring and control system triggers the robotics to change out thecomponent with an appropriate replacement part. Additionally, the datamonitoring and control system has the ability to send electronicinformation such as email or a message on a communications pager orphone system to a pre-determined user.

In one embodiment, upon instruction from a control unit, the insert maybe replaced or substituted in an automated fashion via robotics. The“plug and play” or quick connect fittings are released by thecompression system allowing robotics to remove and replace the insert.The insert may be of the same type or a different variety. This allowsfor a replacement of a malfunctioning components or for substitution ofa different type of separation for varying applications. (Such ascolumns with different stationary phases, or the like.) The emitter maybe replaced along with the column or remain in the system and similarlyreconnected to the replacement column.

In one embodiment, upon instruction from a control unit, the sprayemitter may be replaced or substituted in an automated fashion viarobotics. The “plug and play” or quick connect fittings are released bythe compression system allowing robotics to remove and replace the sprayemitter. The spray emitter column may be of the same type or a differentvariety. This allows for a replacement of a malfunction of worn-outpart(s) or for substitution of a different type of emitter for varyingapplications. The column may be replaced along with the emitter orremain in the system and similarly reconnected to the spray emitter.

The type of column is not limited to any one type and can includeaffinity, reversed-phase, normal phase, carbon phase, monolithic-based,ion exchange, antibody, trap, guard, solid phase, molecular weight, andthose alike. Furthermore, this functionality could be either serial ororthogonal in nature, with a single column or plurality of columns.

The replacement mechanism may be made by such techniques as a roboticarm with pick-a-place, cassette-to-cassette, cartridge-based, pre-loadedmagazine, or those alike. The inserts would be casted, pre-casted,molded, machined, or compiled substrate devices.

FIG. 32 shows a diagram where a plurality of inserts operating orrobotically manipulated as a linear or radial array. The use of theinserts could be serial or parallel in nature. Parallel inserts allowsdifferent inserts to be quickly interchanged, or a second insert may beused while the first insert undergoes a conditioning treatment such as awash or bake. In another embodiment, there may be multiple insertswithin cartridges that are manually or robotically replaced. The castingmay have other features such as ports for makeup fluids or gases. In oneembodiment the final packaged device can have ports and architecture forentry and directional delivery of a nebulizing gas to the spray region.

The inserts of the system can have automated replacement or substitutionof parts. The replacement or substitution may be conducted via apick-and-place approach or via an array such as a linear or radialarray. The device may used in parallel for conducting a simultaneousanalysis, used in sequence, or in a staggered fashion.

In one embodiment, the column, connection fittings, sensors and majorityof the spray emitter (the emitter end must be exposed for properoperation) are encased in a single package. This is accomplished with apreformed structure of multiple inserts or by casting the column,sprayer, sensors, and fittings as one integrated insert such that theyare protected from damage or tampering during use or handling. Thefittings and sensors can be fixed in place such that they are maintainedin an accurate and precise position. The end of the spray emitter may betemporarily covered by a retractable sheath structure to protect thedevice until installation and operation of the system. The insert ismade of thermally conductive materials when temperature control isdesired. The insert may be made into any shape that allows forintegration with the accepting hardware, such as being keyed for preciseand accurate placement, and for aligning of the sensor interconnections.In one embodiment the insert may have features allowing a gas or liquidto enter into the device for thermal control, or may be thermallyconductive to conduct heat or cold to the inner parts such as thecolumn. Additionally, the insert contains other partial detectorscomponents such as optical windows for ultraviolet detection or exposureto the chemical stream for chemical detectors such as oxidation,reduction, or electrochemical reactions. In one embodiment the insertincorporates alignment features for positioning into the receivinghardware, windows for optical, absorbance, refractive index, orfluorescence detection and access ports for additional fluidicmanipulation such as splitting flow or providing make-up flow.

EXAMPLE

A nanoLC column is constructed and coupled to a nanoelectrospray emitter(the emitter can be the same substrate or a separate substrate andcoupled). A “plug and play” fitting is placed on the column's inlet anda second fitting is placed on the column's exit if the column andemitter are to be separate substrates. Conductive sensors with leads areplace at the column inlet and between the column's exit andnanoelectrospray emitter connection. All critical alignments are madeand the device is casted in a curable or hardening agent (such as apolymer) except for the column inlet and a partial zone at the sprayemitter's end. The casting/mold creates an insert in a shape that fitsinto an accepting device in an accurate and precise orientation. Aprotective, retractable sheath is incorporated and positioned over thespray emitter end, eliminating the potential for damage by humanintervention. The device is now protected and components are fixed inplace. The compiled liquid chromatography electrospray device can beplaced manually or automatically via robotics into the receivinghardware, and the column inlet connection is made manually orrobotically via a compression mechanism device. The receiving hardwarealso has corresponding electrical contacts to the sensors and uponplacement of the device in the hardware contacts are made. Anelectrospray current sensor is located in close proximity to theelectrospray region. Column pressure and flow sensors are locatedpre-column. Upon system start up, a control data system monitors thesensors and records baseline values. Control electronics and a datasystem monitor the sensors during system operation. In combination thesensors now monitor system operation. For example if the spray sensingsignal decreases and a leak is detected at the column exit/emitterinterface, the emitter is malfunctioning, or if the spray current sensorsignal is low and a leak is detected at the column inlet, the column orcolumn connection is malfunctioning. Additional sensors diagnose otherparts of the hardware such as the pumps and the injector system. If noleaks are detected at either the column or the sprayer, ion current islow, and the pump pressure decreases, the autosampler maybemalfunctioning. The user can configure the sensors and the informationthe sensors provide as appropriate, to monitor system performance.

Although the preferred embodiment of the present invention is shown, itwill be understood that those skilled in the art that other embodimentscan be used without departing from the scope of the invention. Forexample, in the fitting assemblies shown in the figures, the ferrulesand receiving ports can be interchanged.

The invention has been described with reference to a preferredembodiment. However, it will be appreciated that variations andmodifications can be effected by a person of ordinary skill in the artwithout departing from the scope of the invention.

1-23. (canceled)
 24. A system for the automated compression connectionof fluidic components comprising: receiving hardware comprising aconduit having an exit opening with a first mating surface of acompression connection and configured to align an insert placed therein;an interchangeable plug-and-play consumable insert configured forautomated connection and comprising a conduit having an entry openingwith a second mating surface of the compression connection; a driveforce mechanism; and at least one mechanical support, wherein the driveforce mechanism and the at least one mechanical support are each locatedin the receiving hardware, wherein the insert placed therein is disposedbetween the at least one mechanical support and the drive forcemechanism, and wherein the drive force mechanism is configured to applya substantially axial drive force opposed by the at least one mechanicalsupport to align and compress the first and second mating surfacestogether and create a leak-resistant seal at the compression connectionbetween the insert and the receiving hardware, such that the systemprovides automated alignment and sealing of the insert.
 25. The systemof claim 24, wherein the interchangeable plug-and-play consumable insertcomprises an electrospray emitter.
 26. The system of claim 24, whereinthe interchangeable plug-and-play consumable insert comprises achromatography column and electrospray emitter.